Abstract: Nearly 5 million people in the US are afflicted with heart failure with an additional 550,000 new cases diagnosed each year. Despite current treatment regimens, heart failure still remains the leading cause of morbidity and mortality in the US and developed world because of the failure to adequately replace lost ventricular myocardium from ischemia-induced infarct. Though cell-based therapies to repair the heart have been attempted, they currently have not resulted in long-term improvement due to the inability of human pluripotent stem cells or cardiac progenitor cells to fully differentiate into mature and functional ventricular cardiomyocytes for human cardiac regenerative repair. Toward this end, we have discovered a novel and exciting paradigm for cardiac regeneration that involves cardiac reprogramming and transdifferentiation. Further mechanistic insight into this biologic process will provide an innovative approach to the long-standing issue of programming potential cellular regenerative sources into functional ventricular myocardium for human cardiac regeneration. Thus, utilizing a multi-disciplinary and translational approach, I propose to build from our exciting results and develop novel strategies towards further understanding the fundamental mechanisms of cardiac transdifferentiation with the eventual goal of applying these insights for directed human cardiac cellular programming. These approaches have the real potential to not only revolutionize our understanding of cardiac cellular programming but also provide a safer and more functional source of ventricular myocardial replacement for injured ventricles in heart failure patients. Public Health Relevance: Despite current treatment regimens, heart failure still remains the leading cause of morbidity and mortality in the US and developed world because of the failure to adequately replace lost ventricular myocardium from ischemia-induced infarct. Though cell-based therapies to repair the heart have been attempted, they currently have not resulted in long-term improvement due to the inability of human pluripotent stem cells or cardiac progenitor cells to fully differentiate into mature and functional ventricular cardiomyocytes for human cardiac regenerative repair. Thus, utilizing a multi-disciplinary approach, I propose to build from our new cardiac transdifferentiation paradigm and develop novel strategies towards further understanding the fundamental mechanisms of this biologic event with the eventual goal of applying these insights for directed human cardiac cellular programming.